ABSTRACT
Stemming from work on a previous clinical candidate, loviride, and other alpha-APA derivatives, a new series of potent non-nucleoside reverse transcriptase inhibitors (NNRTIs) has been synthesized. The ITU analogues, which contain a unique diarylated imidoyl thiourea, are very active in inhibiting both wild-type and clinically important mutant strains of HIV-1.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Imines/chemistry , Imines/pharmacology , Thiourea/chemistry , Thiourea/pharmacology , Acetamides/chemistry , Acetamides/pharmacology , Acetophenones/pharmacology , Aniline Compounds/chemistry , Anti-HIV Agents/chemical synthesis , Drug Design , Drug Evaluation, Preclinical , Drug Stability , HIV Reverse Transcriptase/drug effects , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , Structure-Activity Relationship , Thiourea/analogs & derivativesABSTRACT
A synthesis program directed toward improving the stability of imidoyl thiourea based non-nucleoside reverse transcriptase inhibitors (NNRTIs) led to the discovery of diaryltriazines (DATAs), a new class of potent NNRTIs. The synthesis and anti-HIV structure-activity relationship (SAR) studies of a series of DATA derivatives are described.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , HIV Reverse Transcriptase/antagonists & inhibitors , Anti-HIV Agents/chemical synthesis , Drug Design , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , HIV-1/genetics , Inhibitory Concentration 50 , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity Relationship , Triazines/chemistryABSTRACT
The synthesis and anti-HIV-1 activity of a series of diarylpyrimidines (DAPYs) are described. Several members of this novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs) are extremely potent against both wild-type and a panel of clinically significant single- and double-mutant strains of HIV-1.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Nitriles/chemistry , Nitriles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacology , Drug Evaluation, Preclinical , HIV Reverse Transcriptase/antagonists & inhibitors , HIV Reverse Transcriptase/drug effects , HIV Reverse Transcriptase/genetics , HIV-1/drug effects , HIV-1/genetics , Inhibitory Concentration 50 , Mutation , Reverse Transcriptase Inhibitors/chemistry , Reverse Transcriptase Inhibitors/pharmacology , Structure-Activity RelationshipABSTRACT
In previous papers, we have described the discovery of a new series of compounds, 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)- ones, TlBO (1 and 1a), with potent anti-HIV-1 activity and the synthesis of analogues to better define the structure-activity relationships (SAR) in terms of changes in substituents at the N-6 position and variations of the five-membered urea ring as well as the seven-membered diazepine ring. This paper describes the synthesis of TlBO analogues with various substitutents on the aromatic ring and their SAR in terms of anti-HIV-1 properties. Substituents on the 8-position furnished the most rewarding results and gave a large improvement in potency versus the parent compound. These included halogen, thiomethyl, and methyl. Analogues like 8-cyano, -methoxy, and -acetylene were equipotent, while 8-amino, -acetylamino, -dimethylamino, and -nitro were inactive (Table 1). Substituents at the 9-position tended to have little effect on activity, and 10-substituents decreased activity. The 8-chloro compound 6a with IC50 = 0.0043 microM is currently under clinical development.
Subject(s)
Antiviral Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , HIV-1/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Antiviral Agents/pharmacology , Cell Line , Cytopathogenic Effect, Viral/drug effects , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
4,5,6,7-Tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2 (1H)-ones (TIBO), 1, have been shown to significantly inhibit HIV-1 replication in vitro by interfering with the virus's reverse transcriptase enzyme. They have also demonstrated potential clinical efficacy in combating HIV-1, on the basis of a preliminary study. Our prior publications have discussed the discovery of this series of compounds and reported some preliminary chemical and biological studies around N-6 substitutions and 5-membered ring variations of 1. This manuscript describes our synthetic endeavors around 4, 5, and 7 mono- and disubstitutions of 1 and discusses related HIV-1 inhibitory structure-activity relationships. On the basis of inhibition of HIV-1's cytopathic effects in MT-4 cells, we found that 5-mono-Me-substituted analogues, the original substitution in the early lead compounds, and 7-mono-Me-substituted analogues of 1 were comparable as being consistently the most active compounds. Although generally less active, the 4,5,7-unsubstituted, 4-mono-substituted, cis- and trans-5,7-di-Me-substituted, and cis-4,5-di-Me-substituted analogues of 1 also exhibited some significant desired activity. The remaining trans-4,5-di-Me-substituted, cis- and trans-4,7-di-Me-substituted, and all 4,5-, 5,6-, 6,7-, and 7,8-fused disubstituted analogues of 1 possessed no noticeable desired activity.
Subject(s)
Antiviral Agents/chemical synthesis , Benzodiazepines/chemical synthesis , Benzodiazepines/pharmacology , HIV-1/drug effects , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Antiviral Agents/pharmacology , Cell Line , Structure-Activity Relationship , Virus Replication/drug effectsABSTRACT
A series of 2-(aryl- or alkylethynyl)benzenealkanamines were synthesized. They exhibit antihypertensive activity in spontaneously hypertensive rats and coronary vasodilator activity with minimal negative inotropic activity in the "Langendorff" guinea pig heart in vitro. They have been shown to exert their activity by inhibition of Ca2+ influx across cell membranes. Optimal activity is found among the N-(arylethyl)-5-methoxy-alpha-methyl-2-(phenylethynyl)ben zeneethanamines and -propanamines.
